A fetal regressor, Mullerian Inhibiting Substance (MIS), is produced by the male mammalian testis early in gestation and initiates regression of the Mullerian duct, the anlagen of the uterus, fallopian tubes, and proximal vagina. The underlying hypothesis of this proposal is that a fetal regressor which initiates morphogenic dissociation of an organ system in the embryo may produce the same effects against tumors derived from the cell types which respond to the fetal regressor in embryonic life. Initial studies have demonstrated that semipurified fractions with high biological activity for MIS elicited significant cytotoxic effects against a human ovarian cancer in tissue culture. The studies outlined in this proposal attempt to extend these observations to other tumors of Mullerian duct origin in monolayer culture, in soft agar, and in nude mice in vivo, to determine if MIS has potential for clinical application as a chemotherapeutic agent. MIS will be purified in the cytotoxicity of purified fractions tested in vivo and in vitro in tumors of Mullerian duct origin. A monoclonal antibody and a radioimmunoassay will be developed. mRNA will be isolated and recombinant DNA techniques used to produce MIS DNA in bacteria. Ultrastructural studies with labelled MIS and antibody to MIS with defector cell and the target cell will be used to investigate mechanisms of duct regression. The mesenchymal-epithelial interactions that appear to be such a prominent part of Mullerian duct regression, will be studied in depth. This unique system which links cell death with a hormonal signal may yield important clues and interesting new clinical applications to cancer chemotherapy. The availability of purified material with the application of the powerful tools of recombinant DNA and hybridoma technology may provide us with a unique opportunity to study these mechanisms at the gene-translational level.